Studies carried out in mice have demonstrated that two approved drugs — varespladib and marimastat — were effective in countering systemic and lethal effects of Russell’s viper (Daboia russelii) venom either individually or in combination. The two drugs were tested against Russell’s vipers venom sourced from different States across India. Russell’s vipers are responsible for over half of India’s snakebite cases. The study led by Dr. Kartik Sunagar, Professor, Centre for Ecological Sciences at IISc, Bangalore, was published recently in the journal Communications Medicine.
Dr. Sunagar and his team are now working with ICMR to design a human clinical trial to test the two drugs. “During the trial, the drugs will be used as an ancillary treatment to determine how effective they would be in treating snakebites,” he says. The control group control will receive only the antivenom but not the drugs.
Phospholipase A2 (PLA2), and Snake Venom Metalloproteinase (SVMPs) are two main components of Russell’s viper snake venom. These toxins interfere with components of the blood clotting cascade to induce anticoagulant and haemorrhagic effects in humans. While the varespladib drug inhibits PLA2, the marimastat drug inhibits SVMP.
Venom influencing factors
“In a 2021 study, we found differences in venoms of Russell’s vipers from across India depending on the biogeography where they were found. In a follow-up study, we showed that diet and development probably had a major influence in dictating the differences in the venom of Russell’s viper,” says Dr. Sunagar. “Another study published recently [April 2025] found that climatic conditions, such as temperature and rainfall, can also indirectly have a small effect on venom variation.”
“In the Western Ghats, characterised by heavy rainfall and dense forests, a rich variety of amphibians and arthropods thrive, providing snakes with a diverse diet. In contrast, arid regions experience limited rainfall and sparse plant cover, resulting in reduced diversity of prey available for snakes,” Dr. Sunagar says. “Temperature can also influence gene expression, though the extent to which this affects venom variation remains unclear. However, it is likely that temperature changes indirectly alter venoms by affecting the availability of prey composition in the region.”
Differences in venom
In the latest study, Russell’s viper venom from Punjab and Tamil Nadu exhibited the highest PLA2 activity, followed by other regions — Kerala, Maharashtra, Goa, and Madhya Pradesh. Russell’s viper snake venom from all other regions exhibited minimal PLA2 activity. Proteinase activity was highest in Karnataka followed by the Rajasthan, Madhya Pradesh, Goa, and Andhra Pradesh regions. In contrast, venom from Tamil Nadu exhibited little to no activity, while venom samples from other regions exhibited modest proteolytic activity.
Effectiveness of drugs
The PLA2 inhibitor varespladib was found to neutralise even the high PLA2 activity of the venom found in Tamil Nadu and Punjab. The varespladib drug effectively inhibited the modest PLA2 activity of the venom from other Indian regions. In the case of the matrix metalloprotease-inhibiting drug, marimastat, the drug effectively inhibited the venom in a concentration-dependent manner. The drug was effective even when the proteolytic activity was high, as seen in Karnataka. As expected, the drug exhibited highly potent inhibitory effects against the venom with moderate activity, as seen in Madhya Pradesh, Rajasthan, and Goa.
Overall, the drugs varespladib and marimastat when used individually or in a therapeutic drug combination were found to be very effective in reducing venom-induced cytotoxicity, venom-induced coagulopathy, and fibrinogenolysis. When used individually, the drugs were effective in reducing the venom-induced cytotoxicity by snake populations from some regions while being less effective in the case of venom from some other regions. However, the therapeutic combination of varespladib and marimastat nearly completely inhibited these activities.
To replicate the real-world scenario and to test the effectiveness of the drugs after the venom challenge, the researchers administered the drug 30 minutes after venom delivery.
Rescue experiments involving PLA2-rich snake venom from Punjab revealed that the varespladib drug conferred complete protection against venom-induced lethality even when the drug was administered 30 minutes after venom injection. In contrast, marimastat was ineffective in rescue experiments even when the drug was administered soon after venom delivery. In the case of venom from Karnataka, the Marimastat drug provided only 40% survival rate against the SVMP-rich venom at the end of 24 hours even when the drug was administered soon after venom injection.
In the case of venom from Madhya Pradesh, which is rich in both SVMP and PLA2, varespladib and marimastat individually provided only 60% and 40% protection, respectively, when dosed immediately after venom challenge. But a therapeutic combination of the two drugs conferred complete protection from venom-induced lethality even when the drugs were administered 30 minutes after venom injection.
According to Dr. Sunagar, since the body size of mice is extremely small, where they weigh between 18-22 grams, 30 minutes delay in administering the drug is perhaps equivalent to many hours delay in treating patients bitten by a Russell’s viper.
Designing a trial
Even in a single State, the snakes might be producing a different type of toxin in different parts of the State. For instance, in Karnataka, one drug is effective in the southern part of the State, while the other drug is effective in the northern part of the State. “Given this stark variation in venoms, clinical trials must be conducted across various regions of India. Initially, we will begin the clinical trials in select regions and gradually expand them to cover most areas throughout the country. Once the trials are completed, we will determine which drug(s) are necessary for treatment in each specific region,” Dr. Sunagar says. The targeted approach will help in treating patients with a single effective drug or the drug combination instead of blindly using the two drugs in combination across the country and thereby reducing dose effectiveness.
Published – June 18, 2025 12:43 pm IST